Modulation of Intrinsically Disordered Protein Function by Post-translational Modifications

Abstract

Post-translational modifications (PTMs) produce significant changes in the structural properties of intrinsically disordered proteins (IDPs) by affecting their energy landscapes. PTMs can induce a range of effects, from local stabilization or destabilization of transient secondary structure to global disorderto-order transitions, potentially driving complete state changes between intrinsically disordered and folded states or dispersed monomeric and phase-separated states. Here, we discuss diverse biological processes that are dependent on PTM regulation of IDPs. We also present recent tools for generating homogenously modified IDPs for studies of PTMmediated IDP regulatory mechanisms.The amino acid sequences of intrinsically disordered proteins or protein regions (often simply referred to as IDPs) 3 determine their inability to fold into stable tertiary structures under physiological conditions and instead enable them to rapidly interconvert between distinct conformations to mediate critical biological functions (1, 2). The amino acid compositions of IDPs range from very low complexity with little diversity in residue types to much higher sequence complexity that enables disorder-to-order transitions upon binding or post-translational modifications (PTMs) (3-5). This range of sequence composition leads to heterogeneous ensembles with variable hydrodynamic properties and fluctuating secondary and tertiary structure, with some IDPs able to self-associate in phaseseparated protein-dense droplets (6 -11). Structural heterogeneity and dynamic fluctuations endow IDPs with unique advantages over folded proteins for certain roles (12-14). IDPs expose, at least transiently, their entire primary sequence for binding, enabling multiple interactions along their polypeptide chains. This makes them hubs in protein complexes and integrators in signaling networks (15)(16)(17)(18)(19). IDPs also facilitate the multivalent interactions that drive phase separation, underlying cellular membraneless organelles and signaling puncta (20 -22).Due to their accessibility to modifying enzymes, IDPs are the predominant sites of PTMs, which significantly expands their functional versatility (3,23). By changing the physicochemical properties of the primary sequence, PTMs induce a range of structural changes, from local stabilization or destabilization of transient secondary structure to more global conformational changes in disorder-to-order transitions (24, 25). As the hydrodynamic properties of IDPs are strongly affected by electrostatic effects, PTMs that change charge (e.g. phosphorylation and acetylation) can modulate compactness (9 -11). PTMs can also lead to complete state changes, between disordered and folded states (26 -28) or dispersed monomeric and phase-separated states (6,8,22). The scope of PTM-mediated structural and dynamic changes described in recent biophysical and biochemical studies of IDPs is similar to those due to binding to other proteins, nucleic acids, lipids, carbohydrates, ions, cofactors, and other small molecul...

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